Tremendous advances are being made in human gene mapping, statistical methods, and diagnostic assessment of the Affective Disorders. The discovery of linkage between genetic markers on two different chromosomes and Bipolar Disorder makes it imperative that additional families be studied to identify additional susceptibility genes which lead to the illness. This is a new five year proposal to search for genetic linkage in two large multigenerational pedigrees which are segregating the Bipolar form of Manic Depressive Illness. One pedigree includes 47 living members and the other 350. Many members of both families are affected with Bipolar and Unipolar forms of the illness. Our very large kindred is drawn from an insular religious community, which has proven optimal for genetic studies since non-genetic sources of variation are minimized. Deterministic simulation studies have shown that each of the two pedigrees can be used to detect linkage using only the Bipolar phenotype. Accordingly, this study will be robust in the face of genetic heterogeneity. Preliminary studies of the large kindred in this proposal have excluded X-chromosome transmission and the insulin-HRASI region of chromosome 11. This family is therefore segregating a form of Bipolar Manic Depressive Illness which has not yet been ascribed to a specific chromosomal region. In the proposed study, standardized clinical assessments (SADS-L) will be administered at two points in time to minimize instability of diagnosis and to accurately assess important parameters such as age of onset, incident cases and changes in polarity. New methods for the incorporation of repeated measures into segregation and linkage analyses are being developed so that the power of the study to detect genetic loci will be maximized. Restriction fragment length polymorphism (RFLP) studies will be conducted to test the hypothesis of genetic linkage with markers shown to be linked to Affective disorders in other pedigrees. A systematic survey of the entire genome will be conducted to locate the susceptibility locus in each pedigree.